Application of C-H Functionalization in the Development of a Concise and Convergent Route to the Phosphatidylinositol-3-kinase Delta Inhibitor Nemiralisib

Article abstract of DOI:10.1021/acs.oprd.0c00486

This paper describes the development of an improved and scalable method for the manufacture of nemiralisib, a phosphatidylinositol-3-kinase delta inhibitor. Incorporation of three consecutive catalytic reactions, including a palladium-catalyzed C-H functionalization and an iridium-catalyzed borylation, significantly simplified and shortened the synthetic sequence. The revised route was successfully implemented in a pilot plant on a multikilogram scale to deliver >100 kg of product.

Full text of DOI:10.1021/acs.oprd.0c00486

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Article
Application of C−H Functionalization in the Development of a
Concise and Convergent Route to the Phosphatidylinositol-3-kinase
Delta Inhibitor Nemiralisib
Robert N. Bream, Hugh Clark, Dean Edney, Antal Harsanyi, John Hayler, Alan Ironmonger,*
Nadine Mc Cleary, Natalie Phillips, Catherine Priestley, Alastair Roberts, Philip Rushworth, Peter Szeto,
Michael R. Webb, and Katherine Wheelhouse*
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ABSTRACT: This paper describes the development of an improved and scalable method for the manufacture of nemiralisib, a
phosphatidylinositol-3-kinase delta inhibitor. Incorporation of three consecutive catalytic reactions, including a palladium-catalyzed
C−H functionalization and an iridium-catalyzed borylation, significantly simplified and shortened the synthetic sequence. The
revised route was successfully implemented in a pilot plant on a multikilogram scale to deliver >100 kg of product.
KEYWORDS: catalysis, C−H functionalization, iridium, borylation
he selective insertion of transition metals into un-
Tfunctionalized carbon−hydrogen bonds without prior
activation with a stoichiometric reagent and their subsequent
application to coupling reactions offer huge potential in the
simplification of complex small-molecule synthesis, especially
at process scale.1 In particular, coupling of such organometallic
species in catalytic fashion with aryl and heteroaryl halides
offers an attractive alternative to standard cross-coupling
procedures such as Suzuki−Miyaura,2 Stille,3 Negishi,4
Kumada−Corriu,5 and Hiyama6 reactions. In each of those
procedures, an aryl halide is reacted with an organometallic
species under transition metal catalysis. Both coupling partners
must be preformed and thus synthetically tractable; in many
cases, the organometallic coupling partner is prepared from an
aryl halide itself. In turn, each aryl halide must be made by
functionalization of an aryl ring, a process that requires
stoichiometric reagents and is often unselective,7 potentially
necessitating painstaking purification procedures and generat-
ing halogenated waste streams that can be difficult to dispose.
Considering these factors, it is obvious that C−H functional-
ization processes have the potential to shorten and improve the
economic viability of manufacturing routes to fine chemicals
and pharmaceuticals and significantly reduce the associated
environmental burden. We report herein the incorporation of
two of these reactions into the synthetic route to a molecule in
development for the treatment of respiratory disease.
Despite the extensive development work done on the initial
supply route, numerous issues remained with the route itself
and associated processes. First, the mixture of esters 3 and 4
produced in the first step necessitated a three-step telescope
that took approximately a week to complete in a pilot-plant
setting. Furthermore, polymeric material was produced in the
synthesis of esters 3 and 4 that was carried through the
sequence, resulting in low intermediate purity. We also
demonstrated that these polymers were responsible for stalling
of the Suzuki−Miyaura reaction in the lab, forcing us to rely on
recrystallization and hot filtration of aryl chloride 11 to ensure
that stalling did not occur in the plant. Finally, the synthesis of
4-iodo-6-chloroindazole (5) required seven synthetic steps,
causing this intermediate to account for over 60% of the cost of
materials for the route and to have a long production lead time
(Scheme 2).10 We therefore set about looking for shorter,
cheaper, and more convergent routes to 13.
We considered many synthetic approaches; however, central
to the development of an efficient synthesis of 13 is the
application of methods for orthogonal functionalization of the
4- and 6-positions of indazole to allow sequential formation of
the two biaryl bonds. Application of selective C−H
functionalization protocols would drastically simplify the
starting materials since 4-haloindazoles can easily be accessed
from readily available 3-halo-2-methylanilines11 and precedent
exists in the literature for selective insertion into C−H bonds
Nemiralisib (13) is currently in development as a treatment
for chronic obstructive pulmonary disease (COPD). It is a
selective inhibitor of the delta isoform of the phosphatidyli-
nositol-3-kinase enzyme, which has been implicated in
potentiating the inflammatory response to allergens in the
airways.8 The initial supply route was used to generate 5 kg of
material to fund safety assessment studies and Phase I clinical
trials (Scheme 1).9
Special Issue: Celebrating Women in Process Chem-
istry
Received: October 30, 2020
Published: February 9, 2021
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© 2021 American Chemical Society
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Scheme 1. Initial Enabling Supply Route to Nemiralisib
Scheme 2. Synthesis of 4-Iodo-6-chloroindazole (5) from 2,6-Dinitrotoluene (16)
Scheme 3. Approaches to Selective C−H Functionalization of the Indazole and Oxazole Rings
at the 2-position of oxazoles12 and the 5-position of 1,2,3-
trisubstituted benzenes (Scheme 3).13,14
carbon−hydrogen bonds in both oxazole and indazole
substrates, especially those adjacent to heteroatoms.
We began by investigating the selective insertion of
Initial investigations coupled oxazole ester 3 with iodo- or
palladium at the 2-position of the oxazole ring in 3. Others
have demonstrated that the reactivity can be modulated by
judicious choices of the ligand and solvent.12d A key issue with
our strategy was the potential for insertion into multiple
bromobenzene, guided by literature precedent, and confirmed
that conversion to product with the required selectivity could
be achieved using a combination of Pd(OAc)2, RuPhos, pivalic
acid, and cesium carbonate as the base in toluene.
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Following this positive indication that we could access the
desired reactivity, we attempted the coupling of 4-bromoinda-
zole with oxazole ester 3 under the same conditions; however,
no reaction to give the desired product was observed. This is
perhaps unsurprising in light of Buchwald’s observation that
unprotected indazoles and pyrazoles inhibit cross-coupling
reactions unless very specific conditions are used.15 To explore
further whether it was indeed the free N−H that caused the
observed lack of reactivity, we set about synthesizing a range of
model 4-bromoindazole substrates (Table 1). Protection of
the case of mixtures, the N1 and N2 isomers were separated by
chromatography.
We next assessed the performance of these 4-haloindazoles
in a direct coupling reaction with oxazole ester 3 in a 1:1 molar
ratio using the same RuPhos conditions (Table 2). As was
observed for the attempted reaction in the absence of a
protecting group, coupling was inhibited in cases where the
indazole protecting group was labile under the basic reaction
conditions (Piv, Boc). When a more robust protecting group
was used (THP, PMB, N1-Me2NSO2), the desired product was
formed readily and isolated in good yield.
In the case of THP-protected 4-bromo-6-chloroindazole 31,
a mixture of products from competitive addition into both the
C−Br bond and the C−Cl bond was observed (Scheme 4).
Following this observation, an alternative approach was
evaluated whereby the 6-position could be functionalized
after coupling to the oxazole ring.
Table 1. Synthesis of Various N1- and N2-Protected
Indazoles
Iridium-catalyzed C−H borylation has been the subject of
significant advances in recent years.17 In the case of 1,2,3-
trisubstituted benzenes, borylation is favored at the least
hindered 5-position.18 However, less is known about the
relative ease of borylation of heteroaryl C−H bonds.
Borylation of indazole 24 could potentially occur at H1, H2,
or H3, giving rise to a mixture of mono-, di-, and triborylated
products (Scheme 5).
protecting
group
N1:N2
ratio
combined
yield (%)
conditions
THP
TFA, 3,4-Dihydro-2H-pyran,
EtOAc, 77 °C
Boc2O, DMAP, MeCN, 20 °C
PhSO2Cl, NaOH, Bu4NHSO4,
THF, 20 °C
1:0
86
Boc
PhSO2
2:1
1:0
88
99
Me2NSO2 Me2NSO2Cl, NaOH, Bu4NHSO4,
1:1
1:0
3:1
57
89
79
We subjected indazole 24 to a mixture of [Ir(OMe)COD]2
(0.02 equiv), di-tert-butylbipyridine (0.04 equiv), and bis-
(pinacolato)diboron (1.2 equiv) in refluxing THF. Analysis of
the reaction mixture by HPLC revealed a number of peaks
corresponding to a small amount of residual indazole 24 and a
mixture of mono- and diborylated products, identified by LC−
MS as consisting of pinacol ester and boronic acid species. The
crude mixture was purified by flash column chromatography,
THF, 20 °C
PivCl, DMAP, DIPEA, THF,
Piv
70 °C
PMB
PMBCl, NaOH, Bu4NHSO4, THF,
20 °C
N/A
N/A
TIPS
TBS
N/A
N/A
unstable
unstable
indazoles is often unselective,9,16 although under strongly
acidic or basic conditions selectivity for N1 was achieved. In
and the products were analyzed by H NMR spectroscopy,
1
which revealed that the products were in fact the pinacol
Table 2. Direct C−H Coupling of Oxazole Ester 3 with a Range of Protected 4-Bromoindazoles
crude HPLC area % at 220 nm after 3 h
a
substrate
product
SM
product
isolated yield (%)
17
18
19
20
21
22
23
24
25
26
27
28
29
30
0
0
0
43
44
0
78
88
79
3
0
87
54
89
92
84
−
−
85
0
−
a
Isolated yields after chromatography.
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Scheme 4. Mixture of Products Arising from the Attempt to Couple Oxazole Ester 3 with THP-Protected 4-Bromo-6-
chloroindazole 31
Scheme 5. Potential Selectivity Issues in C−H Borylation of Indazole 24
Scheme 6. Product Distribution from Borylation of Indazole 24, Reported as the Sum of HPLC Area % of Boronic Ester and
Acid Peaks Corresponding to Each Species
Scheme 7. Selective Cleavage of the Undesired C−B bond in 35 upon Heating in Methanol
boronate ester derivatives rather than the boronic acids (i.e.,
partial hydrolysis occurred during HPLC analysis). Products
arising from borylation at the desired position (H1) (32) and
on the oxazole ring (H3) (33) as well as both positions H1 and
indazole C−B bond.19 Treatment with a range of aqueous
acids and bases, including KHF2 in an attempt to generate
potassium trifluoroborates, failed to selectively cleave the
unwanted C−B bond.20,21 However, we were delighted to
discover that simply heating diboronate 35 gently in alcoholic
solvents rapidly and selectively cleaved the oxazole C−B bond,
delivering highly pure mono(pinacol boronate) 32 after
crystallization (Scheme 7).
1
H3 (35) were identified by H NMR analysis; however, no
borylation adjacent to the indazole nitrogen (H2) (34) was
detected (Scheme 6).
Given the tendency of heteroarylboron species to proto-
deboronate during Suzuki−Miyaura reactions, we speculated
that the oxazole C−B bond might be more labile than the
We next optimized the conditions to selectively produce
bisborylated material. Increasing the charge of the boron
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a
Scheme 8. Evaluation of Alternative Borylating Reagents and Solvents for Borylation of Indazole 24
a
The product distributions are represented as sums of HPLC area % of boronic ester and acid peaks corresponding to the indicated species.
Scheme 9. Borylation of 24, Selective Cleavage of the Unwanted Oxazole C−B Bond, and Suzuki−Miyaura Coupling with 4-
Bromoindole
Scheme 10. New Process to Synthesize Oxazole Ester 3, Conversion to Amide 42, and Subsequent Demonstration of C−H
Functionalization with THP-Protected 4-Bromoindazole 17
reactant to 2.8 equiv led to essentially complete consumption
of starting material 24 within 4 h, with pinacol borane in THF
giving the best selectivity for the desired products in a very
focused screen of borylating reagents and solvents (Scheme 8).
This combination was successfully demonstrated on a 2 g
scale, with cooling of the reaction mixture to 50 °C upon
reaction completion before addition of methanol and aging for
30 min to effect selective cleavage of the undesired C−B bond.
The mixture was then cooled to 20 °C and aged for 18 h, after
which filtration provided the desired product 32 in 73% yield
with excellent purity. Suzuki−Miyaura coupling of this species
with 4-bromoindole using the previously developed conditions
afforded product 36 in 88% yield (Scheme 9).9
All that remained to complete the synthesis of nemiralisib
was to introduce the isopropylpiperazine ring in place of the
ester and remove the THP protecting group. However, we saw
an opportunity to further shorten the synthetic route by
introducing the piperazine ring in a more convergent fashion.
The process for generating oxazole ester 3 was improved by
switching the base to DBU and running the reaction in CH2Cl2
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Figure 1. Solvent/base/ligand screening for Pd-catalyzed C−H fuctionalization. All of the experiments were performed with 5 mol % Pd source, 10
mol % ligand (where this was not part of the precatalyst charged), 0.6 equiv of pivalic acid, and 2 equiv of base at 100 °C for 20 h. Catalyst systems:
(A) [1,2-bis(dicyclohexylphosphino)ethane]PdCl2; (B) CataCXium A/Pd(OAc)2; (C) CyJohnPhos/Pd(OAc)2; (D) dichlorobis(chlorodi-tert-
butylphosphine)palladium(II); (E) XPhos PdG2.
a
Scheme 11. Evaluation of the Borylation Conditions for Indazole Amide Substrate 43 and Free N−H Analogue 48
a
The product distributions are expressed as sums of HPLC area % of boronic ester and acid peaks corresponding to the indicated components.
at 0 °C, which avoided transesterification.22 Distillation under
high vacuum gave the product in 55% yield with high purity on
a 70 kg scale (Scheme 10). The distilled product was free from
the polymeric impurities that caused issues in the previous
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Scheme 12. Scaled-Up Process from Oxazole Amide 42 to Pinacol Boronate Ester 45
Scheme 13. Final Scaled-up Synthesis of Nemiralisib (13)
route, but the isolated yield was moderate because of
degradation to a range of impurities during the distillation;
an assay of the organic phases during the workup suggested
>80% solution yield of the desired product, with a small
amount also being lost with the toluene fraction in the
distillation. Although CH2Cl2 is an undesirable solvent from a
sustainability perspective, the cleaner reaction profile and lack
of transesterification justified making the change from
methanol; nonetheless, further work has continued to evaluate
suitable alternatives that give clean conversion to the desired
ethyl ester product, with ethyl acetate showing promise, albeit
resulting in a lower isolated yield to date. Ester hydrolysis23
was performed on a 54 kg scale with LiOH in 87% yield, with
the isolation facilitated by simple adjustment of the pH. Amide
42 was produced via acid chloride 40 and subsequent addition
to isopropylpiperazine in isopropyl acetate, and an isolated
yield of 88% was achieved on a 33 kg scale.
The C−H insertion proceeded in excellent yield under the
conditions developed for the oxazole ester; however, by this
point we had identified an opportunity to improve the cost and
sustainability of the process by switching to the corresponding
indazole chloride 44. This coupling was subjected to
optimization (Figure 1). The switch from RuPhos to XPhos
was attempted because the latter was quoted at a significantly
lower price at the time. The hit with XPhos and potassium
carbonate in cyclopentyl methyl ether (CPME) was the most
favorable from a sustainability perspective as well as from
subsequent work on the isolation demonstrating the potential
to perform the reaction, workup, and isolation in the same
solvent rather than necessitating a lengthy solvent switch.
Further work on related nonproprietary ligands led us to
pursue dicyclohexylphenylphosphine as a potential alternative
to XPhos; however, this gave a significantly higher degree of
bis-C−H functionalization and less reproducible results.
Ultimately, optimization of the XPhos process, including the
use of palladium chloride rather than palladium acetate,
enabled a reduction in the loadings of both the palladium
source and the ligand that was deemed viable for this system
and was successfully implemented on multikilogram scale in
the plant (see Scheme 12).
The borylation was revisited to confirm the optimal
conditions for diborylation of this substrate, with a brief
evaluation of the ligand (3,4,7,8-tetramethylphenanthroline or
4,4′-di-tert-butyl-2,2′-bipyridine), solvent, and performance on
free N−H indazole 48 (Scheme 11). This work demonstrated
3,4,7,8-tetramethylphenanthroline in THF to be optimal and
also showed that free N−H indazole 48 was a poor substrate,
further confirming the need for the THP protecting group in
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this synthetic sequence despite the potential improvement in
green metrics had we been able to avoid the use of protecting
groups.
deprotection could be telescoped by exchange of the solvent
for MeOH by distillation and addition of chlorotrimethylsilane,
generating anhydrous HCl. Acetyl chloride could not be used
in this instance, as it resulted in acetylated impurities that were
challenging to purge. The reaction was quenched with
triethylamine at the end of the deprotection to enable direct
crystallization of the product as the methanol solvate (51) in
81% yield on a 35 kg scale. The final overall process is depicted
in Scheme 13.25
In summary, we have developed a new synthetic route to an
investigational drug for the treatment of COPD, taking
advantage of the power of successive selective C−H
functionalization processes in the context of complex
heterocyclic intermediates. The route is shorter and higher-
yielding than the previous sequence (44% from 4-chloroinda-
zole starting material compared with 25% from 6-chloro-4-
iodoindazole), and the starting materials are cheaper and more
readily available (see above). The route represents the basis of
a potential long-term manufacturing route for nemiralisib.
Further optimization of the selective oxazole monodebor-
ylation and isolation of 45 resulted in a process whereby a
solvent swap to 2-propanol is carried out at 50 °C under
reduced pressure, conditions that not only cleave the undesired
C−B bond but also allow isolation of highly pure pinacol
boronate 45 in 83% yield. Controlling the temperature during
this process avoids cleavage of the indazole C−B bond;
performing the solvent swap at atmospheric pressure (70−80
°C) on a 10 g scale led to >15% indazole deborylation.
Although it was possible to reduce the dimeric iridium catalyst
charge to 0.5 mol % or below while still ensuring complete
borylation at C−H1 when very pure input 43 was used,
residual amide 42 was found to inhibit the reaction. In the
interests of achieving a robust process, a compromise was
reached on 1 mol % [Ir] with 5 mol % ligand, as this enabled a
greater tolerance to carried-over amide 42. Very low Ir levels
(<150 ppm) were retained in the crystallized product, with the
rest being purged to the liquors; this presented options for
future recovery. This borylation process was successfully scaled
up to deliver the required product in 83% yield on a 54 kg scale
(Scheme 12).
The next step in the synthesis was to perform a Suzuki−
Miyaura coupling to complete the carbon skeleton of
nemiralisib. 4-Chloroindole (49) represented a more sustain-
able alternative to 4-bromoindole, and a small, focused screen
was performed in order to select the best catalyst/ligand/
solvent/base combination. XPhos/palladium acetate was
identified as the best catalyst system. Methyl isobutyl ketone
(MIBK) was chosen as the solvent because the solubility
profile enabled reaction, workup and crystallization in a single
solvent. The reaction was worked up with basic aqueous N-
acetylcysteine to extract most of the residual palladium from
the product, allowing facile control of the palladium content in
the active pharmaceutical ingredient.24 Distillation of the
MIBK at atmospheric pressure azeotropically dried the solvent,
which significantly reduced the solubility of 50, allowing direct
crystallization. The reaction was successfully performed on a
50 kg scale, and the product was isolated in 74% yield with no
processing issues (Scheme 13).
Finally, the reduction and deprotection of the advanced
intermediate 50 was investigated. Many reducing agents were
assessed, but even with subsequent stoichiometric addition of
the reducing agent, the reduction typically did not reach
completion. Our initial enabling conditions were to add a
solution of 50 in THF to a solution of DIBAL-H in THF.
Interestingly, the reduction selectivity with respect to aldehyde,
alcohol, and other byproducts was significantly better when the
reaction was performed in this addition mode. This process
still had issues due to the high dilution required and large
quantities of isobutane/isobutene produced upon quenching,
which represented a significant safety concern. Following the
hypothesis that a Lewis acid may improve the reaction profile,
the optimal conditions were found to be the addition of
lithium aluminum hydride (10% w/w in THF) to a solution of
the starting material 50 and aluminum chloride. The reaction
was carefully quenched with the addition of EtOAc to reduce
gas production, followed by addition of triethanolamine and
sodium hydroxide. The high ionic strength of the workup
allowed the aluminum salts to be effectively removed in the
aqueous phase to give a THF solution of the product. The
EXPERIMENTAL SECTION
■
General Methods. All commercially sourced chemicals
and solvents were used as received without further purification.
1H NMR spectra were acquired on a Bruker AV-400 NMR
spectrometer, and chemical shifts are reported in parts per
million relative to tetramethylsilane.
Oxazole-5-carboxylic Acid (39). An aqueous solution of
lithium hydroxide monohydrate (124.5 kg of a solution
prepared from 49.44 kg of lithium hydroxide monohydrate
dissolved in 319 kg of water, 398 mol) was added to a solution
of ethyl oxazole-5-carboxylate (3) (54 kg, 382.7 mol) in water
(54 kg) while the temperature was maintained below 25 °C.
The reaction mixture was stirred for 6.5 h and then
concentrated aqueous HCl (64.8 kg) was added while the
temperature was maintained below 25 °C. The crystallization
mixture was cooled to 5 °C and held for 1 h. The product was
filtered off, washed with cold water (88 kg) and then
isopropanol (171.1 kg), and dried under vacuum at 50 °C to
1
afford the title compound (37.88 kg, 87.4%). H NMR (400
MHz, (CD3)2SO) δH 13.68 (br s, 1H), 8.59 (s, 1H), 7.88 (s,
1H).
(4-Isopropylpiperazin-1-yl)(oxazol-5-yl)methanone
(42). Oxalyl chloride (47.7 kg, 375.8 mol) was added to a
solution of oxazole-5-carboxylic acid (39) (32.88 kg, 290.8
mol) in isopropyl acetate (144 kg) while the temperature was
maintained at 52−58 °C. The temperature was increased to
58.5 °C, and the mixture was stirred for 5 h and then cooled to
20 °C. The reaction mixture was added to a solution of 1-
(isopropyl)piperazine (41) (41 kg, 319.8 mol) and potassium
carbonate (118.4 kg) in isopropyl acetate (348 kg) and water
(103 kg), while the temperature was maintained below 25 °C.
The reaction mixture was stirred for 15 min, and the
temperature was increased to 33 °C. The organic phase
washed with water (191 kg), concentrated under reduced
pressure to 95 L, and cooled to 20 °C. n-Heptane (157 kg) was
added, and the crystallization mixture was stirred for 2 h. The
product was filtered off, washed with n-heptane (157 kg), and
dried under vacuum at 40 °C to give the title compound
1
(57.14 kg, 88.0%). H NMR (400 MHz, CDCl3) δH 7.94 (s,
1H), 7.56 (s, 1H), 3.91−3.73 (m, 4H), 2.75 (spt, J = 6.5 Hz,
1H), 2.63−2.52 (m, 4H), 1.06 (d, J = 6.6 Hz, 6H).
(4-Isopropylpiperazin-1-yl)(2-(1-(tetrahydro-2H-
pyran-2-yl)-1H-indazol-4-yl)oxazol-5-yl)methanone
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(43). Palladium chloride (0.74 kg, 4.2 mol) and XPhos (4.36
kg, 9.1 mol) were suspended in CPME (372 L). 4-Chloro-1-
(tetrahydro-2H-pyran-2-yl)-1H-indazole (44) (36 kg, 152.1
mol), (4-isopropylpiperazin-1-yl)(oxazol-5-yl)methanone (42)
(34.78 kg, 155.8 mol), and potassium carbonate (325 mesh,
35.64 kg, 257.9 mol) were added and rinsed in with CPME
(2.58 kg). A solution of pivalic acid (9.294 kg, 91.0 mol) in
CPME (10 L) was added, followed by a rinse with CPME (10
L). The reaction mixture was vacuum-degassed and backfilled
with nitrogen three times and then heated to reflux for 5 h, and
the contents were cooled back to 40 °C. The reaction mixture
was washed with water (144 L) and then 5% w/v aqueous
sodium chloride solution (151.2 kg), and the organic phase
was concentrated to 288 L under atmospheric pressure. The
reaction mixture was filtered into another vessel, and the filter
was washed with CPME (36 L). Then the filtrate was distilled
down to 108 L under atmospheric pressure. Methylcyclohex-
ane (162 L) was added to the vessel while the temperature was
maintained at 75 °C. The contents were then cooled to 62−65
°C, and the crystallization mixture was seeded with the title
compound (90 g) slurried in chilled methylcyclohexane (0.52
L). The crystallization mixture was held at 62 °C for 30 min,
cooled to 7 °C, and then held at 7 °C overnight. The product
was filtered off, washed with methylcyclohexane (2 × 72 L),
and dried in a vacuum oven at 50 °C to give the title
compound (57.2 kg, 88.9%). 1H NMR (400 MHz, (CD3)2SO)
δH 8.59 (s, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.91 (d,
J = 7.3 Hz, 1H), 7.62 (dd, J = 7.3, 8.3 Hz, 1H), 5.97 (dd, J =
2.0, 9.5 Hz, 1H), 4.03−3.85 (m, 1H), 3.84−3.70 (m, 1H), 3.66
(br s, 4H), 2.72 (spt, J = 6.5 Hz, 1H), 2.57−2.40 (m, 5H),
2.11−1.96 (m, 2H), 1.85−1.68 (m, 1H), 1.68−1.47 (m, 2H),
0.99 (d, J = 6.4 Hz, 6H).
(4-Isopropylpiperazin-1-yl)(2-(1-(tetrahydro-2H-
pyran-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1H-indazol-4-yl)oxazol-5-yl)methanone (45). Pina-
colborane (40.80 kg, 318.8 mol) was added to a stirred
solution of (4-isopropylpiperazin-1-yl)(2-(1-(tetrahydro-2H-
pyran-2-yl)-1H-indazol-4-yl)oxazol-5-yl)methanone (43)
(54.00 kg, 127.5 mol), (1,5-cyclooctadiene)(methoxy)iridium-
(I) dimer (0.864 kg, 1.30 mol), and 3,4,7,8-tetramethyl-1,10-
phenanthroline (1.51 kg, 6.39 mol) in THF (243.2 kg) at 20
°C. The reaction mixture was heated to reflux for 8 h, cooled
to 20 °C, and transferred into a vessel containing isopropanol
(253.8 kg), washing through with THF (23.8 kg). The
contents of the vessel were distilled down to 270 L at 200
mbar, and isopropanol (253.8 kg) was added, after which the
mixture was redistilled down to 324 L at 100 mbar.
CAUTION: to avoid peroxide formation, THF distillate should
be treated with a stabilizer. The crystallization mixture was
heated to 40 °C for 4 h, cooled to 20 °C, and stirred overnight,
and then the product was filtered off, washed with isopropanol
(84.8 kg), and dried in a vacuum oven at 50 °C to give the title
compound (57.35 g, 82.8%). 1H NMR (400 MHz, CDCl3) δH
8.70 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.74 (s, 1H), 5.85 (dd,
J = 2.4, 9.5 Hz, 1H), 4.11−4.03 (m, 1H), 3.97−3.77 (m, 5H),
2.78 (spt, J = 6.4 Hz, 1H), 2.70−2.59 (m, 5H), 2.24−2.14 (m,
1H), 2.14−2.03 (m, 1H), 1.86−1.72 (m, 2H), 1.72−1.62 (m,
1H), 1.40 (s, 12H), 1.08 (d, J = 6.4 Hz, 6H).
1,3,2-dioxaborolan-2-yl)-1H-indazol-4-yl)oxazol-5-yl)-
methanone (45) (50 kg, 91.00 mol), palladium acetate (0.2 kg,
0.89 mol), XPhos (0.65 kg, 1.36 mol), and potassium
phosphate (46.4 kg, 218.6 mol) in MIBK (176 kg) and
water (250 kg). The reaction mixture was vacuum-degassed
and backfilled with nitrogen three times and then heated to 82
°C for 78 min prior to addition of further MIBK (300 L). The
phases were mixed for 30 min and then separated. The organic
phase washed sequentially with an aqueous solution made up
from potassium carbonate (2.75 kg), N-acetylcysteine (5.2 kg),
and water (250 kg) and then with water (250 kg) before it was
concentrated to 300 L at atmospheric pressure. The
crystallization mixture was cooled to 20 °C and stirred for 5
h, and then the product was filtered off, washed with MIBK
(80 kg), and dried under vacuum at 50 °C to give the title
1
compound (36.15 kg, 73.7%). H NMR (400 MHz, CDCl3)
δH 8.72 (s, 1H), 8.38 (br s, 1H), 8.35 (d, J = 1.0 Hz, 1H), 8.06
(s, 1H), 7.81 (s, 1H), 7.52−7.46 (m, 1H), 7.36−7.30 (m, 3H),
6.79−6.75 (m, 1H), 5.84 (dd, J = 9.17, 2.32 Hz, 1H), 4.10−
4.04 (m, 1H), 3.88 (br s, 4H), 3.84−3.72 (m, 1H), 2.76 (spt, J
= 6.5 Hz, 1H), 2.68−2.59 (m, 5H), 2.30−2.12 (m, 2H), 1.86−
1.73 (m, 2H), 1.73−1.64 (m, 1H), 1.07 (d, J = 6.60 Hz, 6H).
2-(6-(1H-Indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropyl-
piperazin-1-yl)methyl)oxazole Methanol Solvate (51).
Aluminum chloride (2.94 kg, 22 mol) was added to THF (216
kg) with stirring until dissolved. (2-(6-(1H-Indol-4-yl)-1-
(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxazol-5-yl)(4-
isopropylpiperazin-1-yl)methanone (34.75 kg, 64.5 mol) (50)
was added to the vessel, washed in with THF (0.5 kg), and the
contents were cooled to 0 °C. A solution of lithium aluminum
hydride in THF (10% w/w, 22.6 kg, 59.6 mol) was added
while the temperature was maintained at less than 20 °C,
followed by a THF (0.9 kg) line wash. The reaction mixture
was stirred for 30 min, and then EtOAc (15.6 kg) was added,
followed by 1 h of stirring. A solution of triethanolamine (2.36
kg) in THF (2.1 L) was added, followed by triethanolamine
(36.8 kg) and then aqueous NaOH (15% w/w, 121 kg). The
phases were separated, and the organic phase washed with
aqueous NaOH (15% w/w, 121 kg). THF (17 kg) was added,
and the solvent was distilled down to 104 L at atmospheric
pressure. A constant-volume distillation (104 L) was
performed by adding MeOH (174 L). CAUTION: to avoid
peroxide formation, THF distillate should be treated with a
stabilizer. MeOH (193.3 kg) was added, followed by
chlorotrimethylsilane (35.8 kg, 329.5 mol), and the reaction
mixture was heated to 50 °C for 3 h, after which time
triethylamine (35.8 kg, 353.8 mol) was added and the
crystallization mixture was cooled to 20 °C. The product
was filtered off, washed with MeOH (2 × 55 kg), and dried
under vacuum at 50 °C to give the title compound (24.80 kg,
1
81%). H NMR (400 MHz, (CD3)2SO) δH 13.43 (br s, 1H),
11.36 (br s, 1H), 8.61 (s, 1H), 8.09 (d, J = 1.2 Hz, 1H), 7.92
(m, 1H), 7.51−7.46 (m, 2H), 7.32 (s, 1H), 7.28−7.22 (m,
2H), 6.61 (m, 1H), 4.09 (q, J = 5.3 Hz, 1H), 3.73 (s, 2H), 3.18
(d, J = 4.9 Hz, 3H), 2.60 (br s, 1H), 2.56−2.40 (m, 4H), 0.94
(d, J = 6.4 Hz, 6H).
(2-(6-(1H-Indol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-
1H-indazol-4-yl)oxazol-5-yl)(4-isopropylpiperazin-1-yl)-
methanone (50). 4-Chloroindole (49) (13.8 kg, 91.04 mol)
was added to a stirred solution of (4-isopropylpiperazin-1-
yl)(2-(1-(tetrahydro-2H-pyran-2-yl)-6-(4,4,5,5-tetramethyl-
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
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AUTHOR INFORMATION
■
Corresponding Authors
Katherine Wheelhouse − Chemical Development,
GlaxoSmithKline Medicines Research Centre, Stevenage SG1
2NY, United Kingdom; orcid.org/0000-0002-1963-
1465; Email: katherine.m.wheelhouse@gsk.com
Alan Ironmonger − Chemical Development, GlaxoSmithKline
Medicines Research Centre, Stevenage SG1 2NY, United
Kingdom; Email: alan.2.ironmonger@gsk.com
Authors
†Robert N. Bream − Chemical Development,
GlaxoSmithKline Medicines Research Centre, Stevenage SG1
2NY, United Kingdom
Hugh Clark − Chemical Development, GlaxoSmithKline
Medicines Research Centre, Stevenage SG1 2NY, United
Kingdom
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Medicines Research Centre, Stevenage SG1 2NY, United
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John Hayler − Chemical Development, GlaxoSmithKline
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Natalie Phillips − Chemical Development, GlaxoSmithKline
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Catherine Priestley − Chemical Development,
GlaxoSmithKline Medicines Research Centre, Stevenage SG1
2NY, United Kingdom
Alastair Roberts − Chemical Development, GlaxoSmithKline
Medicines Research Centre, Stevenage SG1 2NY, United
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Philip Rushworth − Chemical Development, GlaxoSmithKline
Medicines Research Centre, Stevenage SG1 2NY, United
Kingdom
Peter Szeto − Chemical Development, GlaxoSmithKline
Medicines Research Centre, Stevenage SG1 2NY, United
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Michael R. Webb − Chemical Development, GlaxoSmithKline
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00486
Author Contributions
The manuscript was written through contributions of all
authors. All of the authors approved the final version of the
manuscript.
Notes
(9) Edney, D.; Hulcoop, D. G.; Leahy, J. H.; Vernon, L. E.;
Wipperman, M. D.; Bream, R. N.; Webb, M. R. Development of
Flexible and Scalable Routes to Two Phosphatidinylinositol-3-kinase
The authors declare no competing financial interest.
†R.N.B., D.E., A.H., and N.M.C. are former GSK employees.
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https://dx.doi.org/10.1021/acs.oprd.0c00486
Org. Process Res. Dev. 2021, 25, 529−540